Fosfomycin: Mechanism and Resistance

Abstract

Fosfomycin, a natural product antibiotic, has been in use for >20 years in Spain, Germany, France, Japan, Brazil, and South Africa for urinary tract infections (UTIs) and other indications and was registered in the United States for the oral treatment of uncomplicated UTIs because of Enterococcus faecalis and Escherichia coli in 1996. It has a broad spectrum, is bactericidal, has very low toxicity, and acts as a time-dependent inhibitor of the MurA enzyme, which catalyzes the first committed step of peptidoglycan synthesis. Whereas resistance to fosfomycin arises rapidly in vitro through loss of active transport mechanisms, resistance is rarely seen during therapy of UTIs, seemingly because of the low fitness of the resistant organisms. Recently, interest has grown in the use of fosfomycin against multidrug-resistant (MDR) pathogens in other indications, prompting the advent of development in the United States of a parenteral formulation for use, initially, in complicated UTIs. Whereas resistance has not been problematic in the uncomplicated UTI setting, it remains to be seen whether resistance remains at bay with expansion to other indications.

Figure 1.

Fosfomycin and the screen in which it was discovered. (A) Structure of fosfomycin. (B) Schematic of SPHERO assay. Gram-negative rods grown in osmotically protective medium, when treated with inhibitors of peptidoglycan synthesis, will show morphological changes leading to the production of round cells called spheroplasts, which are highly differentiable microscopically from normal rods and debris. The assay was run in plastic trays with wells for growth of cells and the wells viewed, after incubation, with a stereomicroscope.

Figure 2.

Overall reaction performed by the MurA enzyme.

Figure 3.

Fosfomycin-modifying enzymes leading to inactivation of fosfomycin and responsible for fosfomycin resistance. Enzyme names are in bold and are shown with their substrates, metal cofactors, and the end products of their modifying activity. (This figure is adapted from Castañeda-García et al. 2013 and is used under license from Creative Commons, creativecommons.org/licenses/by/3.0.)